JP5853772B2 - Method for producing α, α-difluoroaromatic compound - Google Patents

Description

  The present invention relates to a method for producing an α, α-difluoroaromatic compound.

  An α, α-difluoroaromatic compound is important as an intermediate for medical and agricultural chemicals (for example, Patent Document 1). A typical method for producing the compound includes deoxodifluorination reaction of an aromatic carbonyl compound using DAST or Deoxo-Fluor (Non-patent Documents 1 and 2).

  On the other hand, as a technique related to the present invention, a method for producing a geminal difluoro compound in which hydrogen fluoride is added to a vinyl fluoride moiety of a halogenated alkene or fluorocycloalkene is disclosed (Patent Documents 2 and 3). .

International publication 2011/154298 European Patent No. 0634383 International Publication No. 2002/066409

J. et al. Org. Chem. (USA), 1975, 40, p. 574 J. et al. Org. Chem. (USA), 1999, Vol. 64, p. 7048

  The production methods described in Non-Patent Documents 1 and 2 are not suitable for industrial production because they use expensive fluorinating agents.

In the production methods described in Patent Documents 2 and 3, the product difluoromethylene (CF ₂ ) group is not directly bonded to the aromatic ring (not in the α position), and α, α- It was not intended for difluoroaromatic compounds.

In general, in the production of geminal difluoro compounds, it is known that the yield is greatly influenced by whether or not the CF ₂ group in the target product is directly bonded to the aromatic ring. For example, a method for producing a geminal difluoro compound in which two molecules of hydrogen fluoride are added to the triple bond of an acetylene compound has been reported [J. Org. Chem. (USA), 1979, vol. 44, p. 3872, J.A. Org. Chem. (USA), 1962, 27, p. 4015], 2,2-difluorohexane and 3,3-difluorohexane are obtained in high yields (70% and 75%, respectively), while α, α-difluoroethylbenzene is obtained only in low yields [Liquid] Phase method 18%. Comparative Example 1; 1-bromo-4- (1,1-difluoroethyl) benzene is also less than 5%]. In addition, a deoxodifluorination reaction of a carbonyl compound via an acyl having two trifluoromethylcarbonyloxy (CF ₃ CO ₂ ) groups has been reported [J. Fluorine Chem. (Netherlands), 2010, vol. 131, p. 29, JP-A-1-199922], 1,1-difluorocyclohexane can reproduce the described high yield (91%), but α, α-difluoroethylbenzene cannot be reproduced at all [described yield 90%, Comparative Example 2 Less than 10%, 1-bromo-4- (1,1-difluoroethyl) benzene is also about 15%]. Furthermore, the present inventors have applied for a patent for a method for producing a geminal difluoro compound comprising a step of reacting a fluorine-containing sulfuric acid enol ester with a fluorinating agent (Japanese Patent Application No. 2011-166797 / Geminal Difluoro Compound). Production method), also in this production method, when the CF ₂ group in the target compound was directly bonded to the aromatic ring, the yield was significantly reduced (Comparative Example 3 vs. 4). Therefore, even if Patent Documents 2 and 3 disclose a method for producing a geminal difluoro compound in which hydrogen fluoride is added to a vinyl fluoride moiety, the α, α-difluoro aromatic of the present invention having different structural characteristics is disclosed. Whether it can be suitably employed as a method for producing a group compound has been unclear.

  Under such circumstances, there has been a strong demand for a method for producing an α, α-difluoroaromatic compound that is industrially inexpensive and can be produced with good yield.

A method for producing a geminal difluoro compound in which two molecules of hydrogen fluoride are added to the triple bond of the above acetylene compound is considered to add hydrogen fluoride in a stepwise manner (Scheme 1, Fluorine in Organic Chemistry, Richard). D. Chambers, 2004, Blackwell, p. 76-77). As a result of intensive studies, the present inventors have found that the reason why the yield is low when A is a phenyl group is the first-stage addition process of hydrogen fluoride, and the second-stage addition process proceeds extremely well. And reached the present invention (when A is an alkyl group, it is considered that the two-stage addition process of hydrogen fluoride proceeds well).

  Specifically, the present inventors have found that an α, α-difluoroaromatic compound can be produced by reacting 1-fluoro-1-aromatic ring-substituted ethene with a fluorinating agent. 1-Fluoro-1-aromatic ring-substituted ethenes are those in which the aromatic ring part at the 1-position is an aromatic hydrocarbon group or a substituted aromatic hydrocarbon group, and the two substituents at the 2-position are both hydrogen atoms Are preferred, and the resulting products are particularly important as pharmaceutical and agrochemical intermediates. The fluorinating agent is preferably hydrogen fluoride, or a salt or complex composed of pyridine and hydrogen fluoride, particularly preferably a salt or complex composed of pyridine and hydrogen fluoride, and the desired reaction proceeds smoothly.

  That is, the present invention includes [Invention 1] to [Invention 4] and provides a method for producing an α, α-difluoroaromatic compound. The production method disclosed in the present invention has never been reported before and is novel.

[Invention 1]
General formula [1]:

[In the formula, Ar ¹ represents an aromatic ring group or substituted aromatic ring group, R ¹ and R ² are independently a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group, Ar ¹ And R ¹ , Ar ¹ and R ² , or R ¹ and R ² can form a cyclic structure by a covalent bond. ]
The method includes a step of reacting 1-fluoro-1-aromatic ring-substituted ethene represented by general formula (2) with a fluorinating agent:

[Wherein Ar ¹ , R ¹ and R ² are the same as those in the general formula [1]. ]
The manufacturing method of the (alpha), (alpha)-difluoro aromatic compound shown by these.

[Invention 2]
The 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1] is represented by the general formula [3]:

[Wherein Ar ² represents an aromatic hydrocarbon group or a substituted aromatic hydrocarbon group. ]
The α, α-difluoroaromatic compound represented by the general formula [2] is a 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [4]:

[Wherein Ar ² is the same as in general formula [3]. ]
The method of the invention 1, which is an α, α-difluoroaromatic compound represented by the formula:

[Invention 3]
The method according to Invention 1 or Invention 2, wherein the fluorinating agent is hydrogen fluoride or a salt or complex composed of pyridine and hydrogen fluoride.

[Invention 4]
The method according to Invention 1 or Invention 2, wherein the fluorinating agent is a salt or complex composed of pyridine and hydrogen fluoride.

  The 1-fluoro-1-aromatic ring-substituted ethene and the fluorinating agent used in the present invention can be obtained on a large scale at a relatively low cost. Furthermore, since the reaction conditions employed are relaxed, the selectivity is high and the yield is good. Thus, the present invention is very useful as an industrial production method for α, α-difluoroaromatic compounds.

  In addition, a method for synthesizing the α, α-difluoroaromatic compound represented by the general formula [4] using the 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [3] of the present invention as a raw material is reported. [Tetrahedron (UK), 1990, 46, p. 4255], which requires two steps using an expensive reactant, and the superiority of the production method of the present invention is clear.

  The production method of the α, α-difluoroaromatic compound of the present invention will be described in detail.

  The scope of the present invention is not limited to these descriptions, and other than the following examples, the scope of the present invention can be appropriately changed and implemented without departing from the spirit of the present invention. It should be noted that all publications cited in the present specification, for example, prior art documents, patent documents such as publications and patent applications, other non-patent documents, and books shall be incorporated herein by reference. .

R ¹ and R ² of the ¹ -fluoro-1-aromatic ring-substituted ethene represented by the general formula [1] each independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, or a substituted aromatic ring group. . Among them, both R ¹ and R ² are preferably hydrogen atoms. The alkyl group is a linear or branched chain or cyclic group having 1 to 18 carbon atoms (in the case of 3 or more carbon atoms). The aromatic ring group is an aromatic hydrocarbon group having 1 to 18 carbon atoms such as a phenyl group, a naphthyl group and an anthryl group, or a pyrrolyl group (including a nitrogen protector), a pyridyl group, a furyl group, a thienyl group, an indolyl group. An aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, oxygen atom or sulfur atom such as a group (including a nitrogen-protected form), a quinolyl group, a benzofuryl group and a benzothienyl group. The substituted alkyl group and the substituted aromatic ring group have a substituent in any number and in any combination on any carbon atom or nitrogen atom of the alkyl group and aromatic ring group, respectively. Such substituents include fluorine, chlorine, bromine and iodine halogen atoms, lower alkyl groups such as nitro, methyl, ethyl and propyl, lower haloalkyl groups such as fluoromethyl, chloromethyl and bromomethyl, methoxy Group, lower alkoxy group such as ethoxy group and propoxy group, lower haloalkoxy group such as fluoromethoxy group, chloromethoxy group and bromomethoxy group, lower acyloxy group such as formyloxy group, acetyloxy group, propionyloxy group and butyryloxy group , Lower alkoxycarbonyl groups such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, phenyl group, naphthyl group, anthryl group, pyrrolyl group (including nitrogen-protected products), pyridyl group, furyl group, thienyl group, B Aromatic group such as drill group (including nitrogen protector), quinolyl group, benzofuryl group and benzothienyl group, carboxyl group, protector of carboxyl group, amino group, protector of amino group, hydroxyl group, and hydroxyl group It is a protector. Further, in the substituted alkyl group, any carbon-carbon single bond of the above alkyl group can be replaced with a carbon-carbon double bond or a carbon-carbon triple bond in any number and in any combination (of course, The alkyl group partially substituted for these unsaturated bonds may have the above-mentioned substituents as well, and hydrogen fluoride may be added to these unsaturated bonds. By adopting the preferred reaction conditions, it is possible to selectively carry out only the desired reaction). In the present specification, “lower” means a linear or branched chain or cyclic group (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms. The “aromatic ring group” of the “substituent” is a halogen atom, nitro group, lower alkyl group, lower haloalkyl group, lower alkoxy group, lower haloalkoxy group, formyloxy group, lower acyloxy group, A cyano group, a lower alkoxycarbonyl group, a carboxyl group, a protected body of a carboxyl group, an amino group, a protected body of an amino group, a hydroxyl group, a protected body of a hydroxyl group, and the like can be substituted. Furthermore, pyrrolyl, indolyl, carboxyl, amino and hydroxyl protecting groups are described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. And the like.

Ar ¹ of the ¹ -fluoro-1-aromatic ring-substituted ethene represented by the general formula [1] represents an aromatic ring group or a substituted aromatic ring group. The aromatic ring group and the substituted aromatic ring group are the same as the aromatic ring group and the substituted aromatic ring group described in R ¹ and R ² of the ¹ -fluoro-1-aromatic ring substituted ethene represented by the general formula [1]. is there. Among these, an aromatic hydrocarbon group or a substituted aromatic hydrocarbon group is preferable.

Ar ¹ and R ¹ , Ar ¹ and R ² , or R ¹ and R ² of the 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1] form a cyclic structure by a covalent bond. You can also. Specifically, between Ar ¹ and R ¹ , Ar ¹ and R ² , or R ¹ and R ² , between any carbon atoms (via a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) And in any number and in any combination, a cyclic structure (for example, monocyclic, condensed polycyclic, bridged, spiro ring, ring assembly, etc.) can be formed by a covalent bond [however, Substituents (hydrogen atoms) that cannot participate in covalent bonds are excluded.

As the 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1], Ar ¹ is an aromatic hydrocarbon group or a substituted aromatic hydrocarbon group, and both R ¹ and R ² are hydrogen atoms. Are preferred (corresponding to 1-fluoro-1-aromatic ring-substituted ethenes represented by the general formula [3]).

  1-Fluoro-1-aromatic ring-substituted ethenes represented by the general formula [1] are described in Org. Synth. (USA), 1999, vol. 76, p. 159, Tetrahedron (UK), 1990, 46, p. 4255 and the like can be used for the same production.

  The fluorinating agent is hydrogen fluoride or a salt or complex composed of an organic base and hydrogen fluoride.

  The organic base in the “salt or complex comprising an organic base and hydrogen fluoride” is trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, N-methylpiperidine, 4-methylmorpholine, N, N -Dimethylcyclohexylamine, N, N-dimethylbenzylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, 4, -Dimethylaminopyridine, 4-pyrrolidinopyridine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4. .0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene or the like. However, it is not limited to these, The organic base generally used in organic synthesis can also be employ | adopted. Among them, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,4-diazabicyclo [2.2.2] octane and 1, 8-Diazabicyclo [5.4.0] undec-7-ene is preferred, and triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 1,4-diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] undec-7-ene is particularly preferred. These organic bases can be used alone or in combination.

  The molar ratio of the organic base and hydrogen fluoride in the salt or complex comprising the organic base and hydrogen fluoride may be used in the range of 100: 1 to 1: 100, preferably 50: 1 to 1:50, 25 1 to 1:25 is particularly preferred. "Complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride" or "pyridine ~ 30% (-10 mol%) and hydrogen fluoride ~ 70% (~ 90 mol%) commercially available from Aldrich (Aldrich, 2009-2010 catalog) It is convenient to use a complex consisting of

  As the fluorinating agent, hydrogen fluoride or a salt or complex composed of pyridine and hydrogen fluoride is preferable, and a salt or complex composed of pyridine and hydrogen fluoride is particularly preferable.

  The amount of hydrogen fluoride or a salt or complex comprising an organic base and hydrogen fluoride is hydrogen fluoride relative to 1 mol of 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1]. (HF) may be 0.7 mol or more, preferably 0.8 to 1000 mol, particularly preferably 0.9 to 500 mol.

  In the present invention, 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1] is reacted with a fluorinating agent in the presence of an acid catalyst to produce α, α represented by the general formula [2]. -A difluoro aromatic compound may be obtained with a remarkably good yield. However, by employing the preferred reaction conditions of the present invention, the desired reaction can be carried out smoothly even in the absence of an acid catalyst (an acid catalyst is not essential for the present invention). Such acid catalysts include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, perchloric acid, fluorosulfuric acid, tetrafluoroboric acid, hexafluorophosphoric acid, hexafluoroantimonic acid, boron trifluoride, antimony trifluoride, five Inorganic acids such as antimony fluoride, antimony trichloride, antimony pentachloride, antimony trifluoride dichloride, iodine pentafluoride and iodine heptafluoride, and 2,2,2-trifluoroethanol, 1,1,1, Organic acids such as 3,3,3-hexafluoro-2-propanol, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid and trifluoromethanesulfonic acid . These acid catalysts can be used alone or in combination.

  Reaction solvents include aliphatic hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as toluene and xylene, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and α, α, α -Halogens such as trifluorotoluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethers such as tetrahydrofuran and 2-methyltetrahydrofuran, esters such as ethyl acetate and n-butyl acetate, N, N-dimethylformamide And amides such as 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide. Of these, halogen-based, ether-based, amide-based and nitrile-based are preferable, and halogen-based and ether-based are particularly preferable. These reaction solvents can be used alone or in combination.

  The amount of the reaction solvent used may be 0.0001 L (liter) or more per 1 mol of 1-fluoro-1-aromatic ring-substituted ethene represented by the general formula [1], preferably 0.0005 to 30 L, 0.001 to 15 L is particularly preferable. This reaction can also be carried out neat without using a reaction solvent.

  The reaction temperature may be in the range of −50 to + 150 ° C., preferably −40 to + 125 ° C., particularly preferably −30 to + 100 ° C.

  The reaction time may be within a range of 48 hours, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, and nuclear magnetic resonance. It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

  In the post-treatment, an α, α-difluoroaromatic compound represented by the general formula [2] can be obtained by employing a general operation in organic synthesis. The crude product can be purified to a high purity by activated carbon treatment, fractional distillation, recrystallization, column chromatography or the like, if necessary.

[Example]
Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.

In the fluororesin lining reaction vessel, the following formula:

200 mg (gas chromatography purity 97.9%, 0.974 mmol, 1.00 eq) and methylene chloride 1.00 mL (1.03 L / mol) were added, and 5 After cooling to ℃, 610 mg of a complex composed of pyridine and hydrogen fluoride (hydrogen fluoride content 65.0%, 19.8 mmol as hydrogen fluoride, 20.3 eq) was added (two-phase system), and 5 ° C. at the same temperature. Stir vigorously for 25 minutes. The reaction-terminated liquid is diluted with 5 mL of chloroform, washed with 5 mL of water, washed with 5 mL of 5% aqueous potassium carbonate solution, and the recovered organic layer is subjected to internal standard method (internal standard substance; α, α, α-trimethyl) by ¹⁹ F-NMR. Fluorotoluene), the following formula:

0.978 mmol of an α, α-difluoroaromatic compound represented by the formula: The yield by the internal standard method was 100%. As a result of gas chromatography analysis of the recovered organic layer, the conversion rate and purity were 100% and 98.6% (4-bromoacetophenone was 1.1%), respectively. ¹ H and ¹⁹ F-NMR of the recovered organic layer are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 1.89 (t, 3H), 7.46 (Ar—H, 4H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; 73.93 (q, 2F).

In the fluororesin lining reaction vessel, the following formula:

33.0 g (gas chromatographic purity 90.8%, 149 mmol, 1.00 eq) and 147 mL (0.987 L / mol) of methylene chloride were added, and the mixture was heated to 5 ° C. After cooling, 45.0 g of a complex composed of pyridine and hydrogen fluoride (hydrogen fluoride content: 65.0%, 1.46 mol, 9.80 eq as hydrogen fluoride) was added (two-phase system), and 2 at the same temperature. Stir vigorously for 20 minutes. The reaction-terminated liquid was diluted with 100 mL of chloroform, washed twice with 50 mL of water, washed with 100 mL of 5% aqueous potassium carbonate solution, washed with 50 mL of 10% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Following formula:

A crude product of α, α-difluoroaromatic compound represented by The crude product was quantified by an internal standard method by ¹⁹ F-NMR (internal standard substance: α, α, α-trifluorotoluene), and 140 mmol of α, α-difluoroaromatic compound represented by the above formula was contained. . The yield according to the internal standard method was 94%. From the gas chromatographic analysis of the crude product, the conversion rate and purity were 99% and 92.3% (4-bromoacetophenone was 1.5%), respectively.

By purifying the crude total amount of the α, α-difluoroaromatic compound obtained above by simple distillation (boiling point 71 ° C., degree of vacuum 1.4 kPa), 27.6 g of purified product was recovered. The purified product had a gas chromatography purity of 96.6%. The recovery rate in terms of purity was 86%. ¹ H and ¹⁹ F-NMR of the purified product were the same as in Example 1.

In the fluororesin lining reaction vessel, the following formula:

1.90 g (gas chromatographic purity 97.9%, 9.25 mmol, 1.00 eq) of 1-fluoro-1-aromatic ring-substituted ethene represented by formula (2) and 24.4 mL (2.64 L / mol) of chloroform were added, While accompanying nitrogen gas, 12.7 g (635 mmol, 68.6 eq) of hydrogen fluoride was blown in at 20 ° C. over 20 minutes and stirred at the same temperature for 35 minutes. A post-treatment operation similar to that in Example 1 was performed, and the conversion rate and the following formula were determined by gas chromatography analysis of the recovered organic layer:

The purity of the α, α-difluoroaromatic compound represented by the formulas was 100% and 92.8% (4-bromoacetophenone was 6.2%), respectively. ¹ H and ¹⁹ F-NMR of the recovered organic layer were the same as in Example 1.

In the fluororesin lining reaction vessel, the following formula:

10.0 g (gas chromatographic purity 90.7%, 74.3 mmol, 1.00 eq) and 73.0 mL (0.983 L / mol) of methylene chloride were added. After cooling to 5 ° C., 22.7 g of a complex composed of pyridine and hydrogen fluoride (hydrogen fluoride content 65.0%, 737 mmol as hydrogen fluoride, 9.92 eq) was added (two-phase system), and the same temperature. And stirred vigorously for 1 hour 45 minutes. The reaction-terminated liquid is diluted with 50 mL of chloroform, washed twice with 20 mL of water, washed with 50 mL of 5% aqueous potassium carbonate solution, washed with 20 mL of 10% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Following formula:

A crude product of α, α-difluoroaromatic compound represented by When the crude product was quantified by an internal standard method by ¹⁹ F-NMR (internal standard substance; α, α, α-trifluorotoluene), 60.3 mmol of α, α-difluoroaromatic compound represented by the above formula was contained. It was. The yield by the internal standard method was 81%. The conversion rate and purity were 100% and 96.3% (2.0% acetophenone), respectively, from gas chromatography analysis of the crude product.

The whole amount of the α, α-difluoroaromatic compound obtained above was subjected to simple distillation (boiling point 57 ° C., reduced pressure 5.7 kPa) to recover 5.69 g of purified product. The purified product had a gas chromatographic purity of 99.0%. The recovery rate in terms of purity was 66%. ¹ H and ¹⁹ F-NMR of the purified product are shown below.

¹ H-NMR (reference material; Me ₄ Si, heavy solvent; CDCl ₃ ), δ ppm; 1.92 (t, 3 H), 7.47 (Ar—H, 5 H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; 74.02 (q, 2F).

[Reference Example 1]
To 218 mL (0.995 L / mol) of methylene chloride, the following formula:

4-bromostyrene represented by formula (40.0 g, 219 mmol, 1.00 eq) was added, and the mixture was cooled to 5 ° C., and 106 g (657 mmol, 3.00 eq) of a complex composed of 1 mol of triethylamine and 3 mol of hydrogen fluoride and N-bromosuccinimide 58.5 g (329 mmol, 1.50 eq) was added, and the mixture was stirred at the same temperature for 20 minutes and at room temperature for 6 hours. To the reaction solution, 5% aqueous potassium carbonate solution (300 mL) and 5% aqueous sodium hydrogen carbonate solution (300 mL) were added, extracted with ethyl acetate (300 mL), the recovered aqueous layer was extracted with ethyl acetate (100 mL), and the recovered organic layers were combined and washed with 1N hydrochloric acid (100 mL). Washed with 100 mL of water, washed with 100 mL of 5% aqueous potassium carbonate solution, washed with a mixture of 100 mL of 10% brine and 50 mL of 5% aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Following formula:

75 g of a crude product of 1-bromo-4- (1-fluoro-2-bromoethyl) benzene represented by formula (1) was obtained. The crude ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, heavy solvent; CDCl ₃ ), δ ppm; 3.61 (m, 2H), 5.58 (m, 1H), 7.39 (Ar—H, 4H) .

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; -12.44 (m, 1F).

To 170 mL (0.776 L / mol) of tetrahydrofuran was added the total amount of 1-bromo-4- (1-fluoro-2-bromoethyl) benzene obtained above (219 mmol, 1.00 eq) and 100 mg of phenothiazine. After cooling to 5 ° C., 35.7 g (234 mmol, 1.07 eq) of 1,8-diazabicyclo [5.4.0] undec-7-ene was added, and the mixture was stirred at room temperature for 4 hours and 40 minutes. The salt precipitated in the reaction-finished solution is filtered, washed with 50 mL of n-hexane, 210 mL of solvent is concentrated under reduced pressure from the filtrate, 100 mL of n-hexane is added to the residue, and the precipitated salt is filtered, and n-hexane is filtered. After washing with 100 mL, the filtrate was concentrated under reduced pressure and subjected to simple distillation (boiling point 51 to 83 ° C., degree of vacuum 0.7 to 0.5 kPa) to obtain the following formula:

33.9 g of a purified product of 1-fluoro-1-aromatic ring-substituted ethene represented by the following formula: The purified product had a gas chromatography purity of 90.8%. The total yield from 4-bromostyrene in terms of purity was 70%. ¹ H and ¹⁹ F-NMR of the purified product are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 4.98 (m, 2H), 7.46 (Ar—H, 4H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; 53.65 (m, 1F).

[Reference Example 2]
To 480 mL (0.500 L / mol) of chloroform, the following formula:

100 g (960 mmol, 1.00 eq) represented by the following formula was added, cooled to 5 ° C., 309 g (1.92 mol, 2.00 eq) of a complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride and 188 g of N-bromosuccinimide (1 0.06 mol, 1.10 eq) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature overnight. Wash the reaction solution with 200 mL of 5% aqueous potassium carbonate solution, wash with 100 mL of water, wash with 100 mL of 5% aqueous potassium carbonate solution, wash with 100 mL of 10% brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. According to the following formula:

A crude product of 1-fluoro-2-bromoethylbenzene represented by formula (1) was obtained. The ¹⁹ F-NMR of the crude product is shown below.

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; -12.44 (m, 1F).

To 700 mL (0.729 L / mol) of tetrahydrofuran was added the total amount of crude 1-fluoro-2-bromoethylbenzene obtained above (960 mmol, 1.00 eq) and 400 mg of phenothiazine, cooled to 5 ° C., 1 , 8-diazabicyclo [5.4.0] undec-7-ene (160 g, 1.05 mol, 1.09 eq) was added, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 2 hours. The salt precipitated in the reaction completion liquid is filtered, washed with 100 mL of n-hexane, 500 mL of solvent is concentrated under reduced pressure from the filtrate, the salt precipitated in the residue is filtered, and simple distillation (boiling point: 50 to 67 ° C., (Decompression degree 4.0-3.5 kPa)

77.4 g of a purified product of 1-fluoro-1-aromatic ring-substituted ethene represented by the formula: The purified product had a gas chromatography purity of 90.7%. The total yield from styrene in terms of purity was 60%. ¹ H and ¹⁹ F-NMR of the purified product are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 4.95 (m, 2H), 7.45 (Ar—H, 5H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; 53.85 (m, 1F).

[Comparative Example 1]
In a fluororesin-lined reaction vessel, 220 mg (11.0 mmol, 19.9 eq) of hydrogen fluoride and 0.300 mL (0.543 L / mol) of methylene chloride were added, cooled to 5 ° C., and the following formula:

100 mg (0.552 mmol, 1.00 eq) of 1-bromo-4-ethynylbenzene represented by the formula (2 phase system) was added, and the mixture was vigorously stirred at the same temperature for 2 hours. The reaction-terminated liquid is diluted with 5 mL of chloroform, washed with 5 mL of water, washed with 5 mL of 5% aqueous potassium carbonate solution, and the recovered organic layer is subjected to internal standard method (internal standard substance; α, α, α-trimethyl) by ¹⁹ F-NMR. Fluorotoluene), the following formula:

The amount of 1-bromo-4- (1,1-difluoroethyl) benzene represented by the formula was less than 27.6 μmol. The yield by the internal standard method was less than 5%. The conversion rate and purity were 100% and 0.6% (4-bromoacetophenone was 87.5%) from gas chromatography analysis of the recovered organic layer, respectively.

[Comparative Example 2]
Following formula:

Was added to 1.00 g (8.32 mmol, 1.00 eq) of acetophenone, and 4.37 g (20.8 mmol, 2.50 eq) of trifluoroacetic anhydride was added and stirred at 35 ° C. for 4 days. From the gas chromatographic analysis of the reaction finished liquid, the conversion rate and the following formula:

An acyl having _two CF ₃ CO ₂ groups represented by the formula:

The purity of the trifluoroacetic acid enol ester represented by the formula was 52%, 15.2%, and 16.4%, respectively. A post-treatment operation similar to that in Example 1 of JP-A-1-199922 was performed on the reaction end solution, and a similar fluorination step was performed.

The α, α-difluoroethylbenzene represented by the formula was contained less than 0.832 mmol. The yield by the internal standard method was less than 10%.

  Separately, the same asylation step and fluorination step were performed using 4-bromoacetophenone as a raw material substrate, and the yield of the corresponding 1-bromo-4- (1,1-difluoroethyl) benzene was about 15%. there were.

  On the other hand, cyclohexanone gave 1,1-difluorocyclohexane in a yield of 87%.

[Comparative Example 3]
A fluororesin-lined reaction vessel is immersed in a −5 ° C. refrigerant bath, and 3.45 g (172 mmol, 20.0 eq) of hydrogen fluoride, the following formula:

2.00 g (8.61 mmol, 1.00 eq) of a fluorine-containing sulfuric acid enol ester represented by the following, 0.200 mL (0.0232 L / mol) of chloroform and 196 mg (1.72 mmol, 0.200 eq) of trifluoroacetic acid were added, The mixture was stirred at -5 ° C for 3 hours and 15 minutes. The reaction-terminated liquid was diluted with 10 mL of chloroform, washed twice with 10 mL and 5 mL of water, washed with 10 mL of 10% aqueous potassium carbonate solution, washed with 5 mL of 10% brine, and the recovered organic layer was an internal standard by ¹⁹ F-NMR. When quantified by the method (internal standard substance: hexafluorobenzene), the following formula:

6.59 mmol of the geminal difluoro compound represented by The yield according to the internal standard method was 77%. ¹⁹ F-NMR is shown below.

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; 71.45 (m, 2F).

[Comparative Example 4]
The reaction vessel of the fluororesin lining is immersed in a −5 ° C. refrigerant bath, 1.56 g (78.0 mmol, 19.7 eq) of hydrogen fluoride, the following formula:

1.00 g (3.96 mmol, 1.00 eq) of fluorine-containing sulfuric acid enol ester represented by the following formula: 0.100 mL (0.0253 L / mol) of chloroform and 90.3 mg (0.792 mmol, 0.200 eq) of trifluoroacetic acid. In addition, the mixture was stirred at −5 ° C. for 3 hours. The reaction-terminated liquid was diluted with 5 mL of chloroform, washed twice with 5 mL and 2.5 mL of water, washed with 5 mL of 10% aqueous potassium carbonate solution, and washed with 2.5 mL of 10% brine, and the recovered organic layer was replaced with ¹⁹ F- When quantified by the internal standard method by NMR (internal standard substance; hexafluorobenzene), the following formula:

The geminal difluoro compound represented by was contained less than 0.396 mmol. The yield by the internal standard method was less than 10%.

  The α, α-difluoroaromatic compound targeted in the present invention is important as a pharmaceutical and agrochemical intermediate.

Claims (4)

General formula [ 3 ]:

Wherein, Ar ² is to display the aromatic hydrocarbon group or substituted aromatic hydrocarbon group. ]
A step of reacting 1-fluoro-1-aromatic ring-substituted ethene represented by the formula (1) with one or more fluorinating agents selected from hydrogen fluoride, or a salt or complex consisting of pyridine and hydrogen fluoride , General formula [ 4 ]:

[Wherein Ar ² is the same as the general formula [ 3 ]. ]
The manufacturing method of the (alpha), (alpha)-difluoro aromatic compound shown by these. The method according to claim 1 , wherein the fluorinating agent is a salt or complex composed of pyridine and hydrogen fluoride. Ar of general formula [3] ² The method according to claim 1 or 2, wherein the substituted aromatic hydrocarbon group in has a halogen atom in any number and in any combination on any carbon atom of the substituted aromatic hydrocarbon group. The method according to any one of claims 1 to 3, wherein a halogen-based or ether-based reaction solvent is used.